New research paves the way for potential therapeutic advancements in enhancing regeneration and addressing age-related declines in regenerative capacity.

Health

Cancer, stroke and head injuries can all cause cognitive impairment and, as a result, a degradation in one’s quality of life. But what if the human brain was able to regenerate itself, essentially eradicating any damage caused by injury or disease? That’s the line of thinking that the EU-funded REBUILDCNS project decided to follow. “Certain species such as zebra fish and axolotl have the ability to regenerate their brains,” says Ana Martin-Villalba, a molecular neurobiologist at the German Cancer Research Center. “Even though mammals share the same genes as these other species, we do not share their regenerative capacity.” The project, which received support from the European Research Council, looked to uncover the intrinsic responses and mechanisms within mammals that either inhibit or could potentially facilitate brain regeneration.

The role of the inflammatory response

To start, the project examined the role that the inflammatory response – the immune system’s response to harmful stimuli – plays in regeneration. “While we recognise that regeneration-capable organisms harness inflammation to activate regenerative programmes, this process doesn’t yield significant regeneration in mammals,” explains Martin-Villalba. Here, researchers discovered that interferons, long thought to regulate the inflammatory response to viruses and injuries, also play a pivotal role in stem cell functionality. “Intriguingly, while interferons support stem cell function in a young brain, they prove detrimental in older brains,” adds Martin-Villalba. Stem cells are those cells from which all other cells with specialised functions are generated. To better understand why, the project took a deep dive into DNA methylation – a chemical modification of DNA and other molecules that plays a critical role in the regulation of early development in humans and other mammals.

Advancements in regeneration

What researchers found is that DNA methylation changes define a crucial early waypoint in the making of a stem cell. “We’ve pinpointed DNA methylation as being the key molecular layer that dictates stemness, which itself plays a profound role in the realm of regenerative medicine,” notes Martin-Villalba. Stemness is a cell’s capability for self-renewal and differentiation. In a practical sense, this means that there is considerable hope that, in the future, treating brain injuries, such as from a stroke, could be based on activating the latent neurogenic potential that the brain already has. “This revelation paves the way for potential therapeutic advancements in enhancing regeneration and addressing age-related declines in regenerative capacity,” remarks Martin-Villalba.

Reshaping our understanding of stem cell biology

By pinpointing DNA methylation as the gatekeeper of cell fate in the brain, along with its other findings, the REBUILDCNS project has helped answer a core question of neurobiology. It also suggested a new vantage point for stem cell biology. “Our groundbreaking research has fundamentally reshaped our understanding of stem cell biology, particularly highlighting the potential to manipulate DNA methylation to activate stemness in an otherwise dormant cell and, by extension, enhance the brain’s capacity for regeneration,” concludes Martin-Villalba. “This hints at unprecedented advancements in regenerative medicine.” Researchers are currently working on manipulating DNA methylation to send a cancer cell in the opposite direction it needs to go to regenerate. The hope is to be able to reverse the stemness state of a cancer cell and, in doing so, prevent its growth.

Keywords

REBUILDCNS, brain, brain regeneration, disease, cancer, stroke, head injuries, cognitive impairment, inflammatory response, stem cells, DNA methylation, biology, neurobiology